Morell and Ashwell et al. determined that when a sialyl group of ceruloplasmin is removed by neuraminidase, this plasma protein rapidly disappears from serum. They disclosed that this phenomenon is due to the uptake by the asialoglycoprotein (ASGP) receptor present in liver cells (J. Biol. Chem., 243:155, (1968)). Thereafter, it was reported that the ASGP receptor is present only in liver cells (Adv. Enzymol., 41:99, (1974)). Such specific uptake by liver cells has been identified from the fact that when asialoceruloplasmin or asialoorosomucoid, which is experimentally labeled with tritium, is injected into the living body, the isotope is selectively detected only in liver cells (Scheinberg I. H., Morell A. G., Stockert R. J.: Hepatic removal of circulating proteins. Davidson C. S., ed. Problems in Liver Diseases. pp 279-285, New York, Stratton Company, (1979)). In addition, it was also disclosed that this receptor specifically recognizes and absorbs glycoproteins having D-galactose or N-acetylgalactosamine as the terminal sugar group (Ann. Rev. Biochem., 51:531, (1982)). The cell membrane of liver cells comprises a cell structure which combines with asialoglycoprotein terminated with galactose. This cell structure was first named hepato-binding protein (HBP) but is presently called asialoglycoprotein receptor. Further, it has been observed that among various desialylated glycoproteins, the desialylated alpha(1)-acid glycoprotein, asialoorosomucoid, most rapidly disappears from the serum after injection. Therefore, it has been determined that asialo-alpha(1)-acid glycoprotein is both specifically and well taken up by liver cells (J. Biol. Chem., 245:4397 (1970)). The asialoglycoprotein receptor is constituted with a single polypeptide having a molecular weight of about 40,000 and can recognize a glycoprotein having a galactose residue at the nonreductive terminal position of the saccharide chain (i.e. asialoglycoprotein).
While the physiological functions of an asialoglycoprotein receptor are still uncertain, it is believed that an asialoglyroprotein receptor participates in the metabolism of glycoproteins. In fact, the increase of the blood level of an asialoglycoprotein is observed in case of hepatic diseases such as chronic hepatitis, liver cirrhosis and hepatic cancer. Further, the decrease of the quantity of an asialoglycoprotein receptor is observed in an experimental model of hepatic disorder induced by administration of chemicals. In view of these phenomena, it may be possible to diagnose hepatic diseases through assessment of the quantity and quality of an asialoglycoprotein receptor determined by the use of an asialoglycoprotein-like substance, i.e. an asialoglycoprotein receptor-directing compound.
Asialoglycoconjugates have been covalently linked to other agents as a means of targeting chemical (immunosuppressive drugs) and biological agents (antibodies) to be taken up by the liver for therapeutic and diagnostic purposes (see, U.S. Pat. Nos. 5,346,696, 5,679,323, and 5,089,604)). In addition, localization of bone marrow stem cells and lymphocytes to the liver has been demonstrated (Samlowski, et al., Cell. Immunol. 88:309-322, (1984); Samlowski et al., Proc. Natl. Acad. Sci. 82:2508-2512, (1985)).
It is also known that a large proportion of cells infused into mammals adhere to the lung endothelium, independent of cell type or physiological homing properties. It has been observed that stem cells accumulate in the lungs when they are administered Morrison et al. Nature Medicine 2:1281-1282 (1996); Martino et al. Eur J Immunol 23:1023-1028 (1993); Pereira et al. Proc Natl Acad Sci USA 92: 4857-4861(1993); and Gao et al. Cells Tissues Organs 169:12-20 (2001)).
Orosomucoid, asialo-orosomucoid and agalacto/asialo-orosomucoid have been shown to inhibit neutrophil activation superoxide anion generation, and platelet activation (Costello et al. Clin Exp Immunol 55:465-472 (1984). and Costello et al. Nature 281:677-678 (1979)). These proteins also induced transient immunosuppression and protected against TNF challenge (Bennett et al. Proc Natl Acad Sci USA 77 6109-6113(1980) and Libert et al. J Exp Med 180:1571-1575 (1994). Orosomucoid demonstrated specific binding to pulmonary endothelial cells, which appeared to be independent of carbohydrate recognition sites (Schnitzer et al. Am J Physiol 263:H48-H55 (1992). Moreover, orosomucoid was shown to bind to skin capillary endothelial cells in a dose dependent manner, thereby maintaining normal capillary permeability in the face of inflammatory agonists that caused leakage in control animals (Muchitsch et al. Arch Int Pharmacodyn 331:313-321 (1996)). Similarly, infused orosomucoid bound to kidney capillaries and restored the permselectivity of glomerular filtration (Muchitsch et al. Nephron 81:194-199 (1999)).
A stem cell is a special kind of cell that has a unique capacity to renew itself and to give rise to specialized cell types. Although most cells of the body such as heart cells or skin cells, are committed to conduct a specific function, a stem cell is uncommitted and remains uncommitted, until it receives a signal to develop into a specialized cell. In 1998, stem cells from early human embryos were first isolated and grown in culture. It is recognized that these stem cells are, indeed, capable of becoming almost all of the specialized cells of the body. In recent years, stem cells present in adults also have been shown to have the potential to generate replacement cells for a broad array of tissues and organs, such as the heart, the liver, the pancreas, and the nervous system. Thus, this class of adult human stem cell holds the promise of being able to repair or replace cells or tissues that are damaged or destroyed by many devastating diseases and disabilities. It is highly useful to effect such therapies by targeting stem cells to particular organs of the body.
In the prior art, adult stem cells generally have been presented to the desired organs either by injection into the tissue or by infusion into the local circulation. A need exists to develop methods for delivery of stem cells through the circulation to specific organs. Such methods would provide a means to target non-invasively solid organs such as the liver, heart, lungs and kidneys. In addition, very diffuse tissues, such as the lung, which are not amenable to dosage by injection could be targeted. Such methods would be useful in regenerative stem cell therapies involving such organs as the liver, heart, lungs and kidneys. The present invention addresses these and other needs.